Low oxygen levels in tumors ‘trigger spread of breast cancer’

Researchers have discovered that low oxygen conditions can trigger the production of proteins that contribute to the spread of breast cancer cells. This is according to a study published in the Proceedings of the National Academy of Sciences.

Biologists from Johns Hopkins University found that low oxygen conditions prompted increased production of proteins called RhoA and ROCK1.

cells the ability to move and spread, leading to worse outcomes forbreast cancer patients.

Dr. Gregg Semenza, the C. Michael Armstrong professor of medicine at the Johns Hopkins School of Medicine and senior author of the study, explains that in order to move, cancer cells need to initiate a number of changes to their internal structures.

RhoA and ROCK1 are known to play an important part in the formation of these structures, allowing the creation of “parallel filaments” in cancer cells that enable them to “grab” external surfaces to haul themselves along.

Dr. Semenza says that in many metastatic breast cancers, the genes that code for RhoA and ROCK1 are known to be activated at high levels, but it was unknown as to exactly what causes these levels to become high.

He notes that low oxygen levels often occur in breast cancers and explains the process in detail:

“As tumor cells multiply, the interior of the tumor begins to run out of oxygen because it isn’t being fed by blood vessels. The lack of oxygen activates the hypoxia-inducible factors, which are master control proteins that switch on many genes that help cells adapt to the scarcity of oxygen.”

He adds that these hypoxia-inducible factors switch on genes that enable cancer cells to break away from the tumor that is low in oxygen. The cancer cells are then able to violate the blood vessels in order to spread to other areas of the body.

Hypoxia-induced factors ‘bind’ to RhoA and ROCK1

A breast cancer cell (blue) in a low oxygen condition. It has formed ‘filaments’ (green) that enable the cell to contract, and has grown ‘hands’ (red) that latch on to surfaces to pull itself along. Image credit: Daniel Gilkes.

To investigate this process further, Daniele Gilkes, lead study author from Johns Hopkins University, conducted a series of laboratory studies.

She found that when breast cancer cells were exposed to low oxygen levels, they had significantly more movement compared with breast cancer cells exposed to normal oxygen levels.

In detail, it was found that the breast cancer cells had significantly more “hands” per cell and three times as many “filaments,” meaning they were able to move more.

However, when Gilkes reduced the hypoxia-inducible factors, the breast cancer cells saw reduced movement, as well as a reduced number of filaments and hands.

On measuring RhoA and ROCK1 protein levels in the breast cancer cells, the researchers found that the levels of these proteins increased when the cells were exposed to low oxygen conditions. But RhoA and ROCK1 levels reduced when the hypoxia-inducible factors were reduced.

The researchers say further studies confirmed that hypoxia-inducible factors bind to RhoA and ROCK1 genes and activate them.

Additional research found that breast cancer patients who had high levels of RhoA or ROCK1 proteins were significantly more likely to die from the disease, compared with patients with low levels of the proteins. This finding was more apparent for patients who had high levels of both proteins.

Commenting on the study findings, Gilkes says:

“We have successfully decreased the mobility of breast cancer cells in the lab by using genetic tricks to knock the hypoxia-inducible factors down.

Now that we understand the mechanism at play, we hope that clinical trials will be performed to test whether drugs that inhibit hypoxia-inducible factors will have the double effect of blocking production of RhoA and ROCK1 and preventing metastases in women with breast cancer.”